Non-ionic X-ray contrast agents constitute a very important class of pharmaceutical compounds produced in large quantities 5-[N-(2,3-dihydroxypropyl)-acetamido]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (“iohexyl”), N,N′-Bis(2,3-dihydroxypropyl)-5-[(2-hydroxyacetyl)-(2-hydroxyethyl)amino]-2,4,6-triiodo-benzene-1,3-dicarboxamide (“ioversol”), and 1,3-bis(acetamido)-N,N-bis[3,5-bis(2,3-dihydroxypropyl-aminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane (“iodixanol”) are important examples of such compounds. They contain one or two triiodinated benzene rings.
The industrial production of iohexyl, ioversol, and iodixanol involves a multistep chemical synthesis. The final drug substance must meet the stringent purity standards set forth by regulatory agencies. While purity is of the utmost importance, it is also important to reduce the cost of production by optimizing each synthetic step. Even a small improvement in reaction design can lead to significant savings in a large scale production.
The instant improvement is directed to 5-amino-N,N′-bis(2,3-dihydroxypropyl)-isophthalamide (also known as aminoisophthalic acid bisamide, AIPA bisamid or ABA). ABA is a common intermediate in the industrial preparation of iodixanol and iohexyl. For example, one of the typical synthetic steps in preparing iodixanol is the iodination of ABA using iodine chloride to convert ABA to 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Compound B). See Scheme 1; see also U.S. Pat. Nos. 6,441,235 and 6,274,762. This instant invention is directed to removing substantial amounts of impurities in ABA before its iodination reaction.
